tbuckley/cabot-search huggingface dataset:
Novel metabolic classification for extrahepatic complication of metabolic associated fatty liver disease: A data-driven cluster analysis with international validation
Authors: Junzhao Ye, Xiaodong Zhuang, Xin Li, Xiaorong Gong, Yanhong Sun, Wei Wang, Shiting Feng, Tingfeng Wu, Bihui Zhong
Journal: Metabolism (2022)

BackgroundTraditional classification systems of metabolic-associated fatty liver disease (MAFLD) do not account for the high rate of extrahepatic complications. To create a new classification of MAFLD using metabolic parameters to identify risks of complications more accurately.MethodsThe retrospective study included MAFLD patients from the First Affiliated Hospital of Sun Yat-sen University for model development, and the model was validated respectively using Chinese cohort and UK Biobank database. Cluster analysis with k-means cluster was built using age, body mass index (BMI), glycosylated hemoglobin (HbA1c), total cholesterol/high density lipoprotein cholesterol (HDL-C) ratio, triglyceride, and lipoprotein(a) [Lp(a)] levels. Cox regression models were used to compare the risk of type 2 diabetes (T2DM), chronic heart disease (CHD), stroke and mortality between the clusters.Results1038 MAFLD patients from cross-sectional population were recruited for the model derivation, with 10,451 cases (33.4 % of MAFLD) from Chinese cohort and 304,141 cases (34.9 % of MAFLD, 1010 cases with magnetic resonance imaging proton density fat fraction measurement [MRI-PDFF]) from the international cohort validated. Five replicable clusters of MAFLD patients were identified: Cluster 1(mild obesity and dyslipidemia-related), Cluster 2 (age related), Cluster 3 (severe insulin resistance-related), Cluster 4[high Lp(a)-related], and Cluster 5 (severe mixed hyperlipidemia-related). Patients in different clusters exhibited differences in the development of T2DM, CHD, stroke and all-causes mortality. Patients in Cluster 3 had significantly worst survival outcomes and higher risks of T2DM and CVD than those in other clusters.ConclusionThe novel classification offers improved discrimination of new-onset MAFLD patients with different metabolic complications.
Measuring the longitudinal course of voice hearing under psychological interventions: A systematic review
Authors: Sofia Loizou, David Fowler, Mark Hayward
Journal: Clinical Psychology Review (2022)

Trials of psychological interventions targeting distressing voices have used a range of variables to measure outcomes. This has complicated attempts to compare outcomes across trials and to evaluate the effectiveness of these interventions. Therefore, this review aimed to identify the variables that have been used to measure the longitudinal course and impact of voice hearing under these interventions and to evaluate how these variables change over time. Inclusion and exclusion criteria were applied, resulting in a total of 66 articles. Of these, 60 studies (28 RCTs, 23 uncontrolled, 9 non-randomised) were published in peer-reviewed journals, whilst 6 were recently completed or currently ongoing. The findings of this review suggest that a range of variables that are not directly relevant to psychological interventions have been used (e.g., depression, characteristics of voice hearing experience), whilst those directly impacted by psychological interventions (e.g., voice-related distress), broader concepts of outcome (e.g., functioning) and specific associated processes (e.g., self-schema) have received less attention. Findings also showed that the majority of variables demonstrated improvements, but effect sizes varied considerably across trials. This may be attributed to methodological differences such as statistical power, blinding, control groups and different methods of measurement. Our review highlights the importance of determining a set of outcomes that are directly targeted and should change under psychological interventions. Recommendations include the use of voice-related distress as a primary outcome. This can ultimately facilitate comparisons across studies and inform the development of psychological interventions.
Roll-out of HIV pre-exposure prophylaxis use in France: A nationwide observational study from 2016 to 2021
Authors: Sophie Billioti de Gage, David Desplas, Rosemary Dray-Spira
Journal: The Lancet Regional Health - Europe (2022)

Oral HIV pre-exposure prophylaxis (PrEP) has been available and fully reimbursed for people at high risk of sexually acquired HIV infection in France since January 2016. Its dissemination has been widely promoted to reduce HIV incidence in high-risk populations. This study aimed to assess the roll-out of PrEP use in France from its implementation until mid-2021.Using the French National Health Data System (SNDS) covering 99% of people residing in France, all PrEP users defined as individuals aged 15 years or older who received at least one dispensing of PrEP between 1 January 2016 and 30 June 2021 were identified. PrEP users number and their socio-demographic and PrEP use characteristics were assessed over time.As of 30 June 2021, a total of 42 159 individuals had initiated PrEP in France. Monthly PrEP initiations increased steadily up to 1027 in February 2020, and then slowed down sharply from the onset of the COVID-19 epidemic until a recovery in the first half of 2021. PrEP users were overwhelmingly men (97·5%, 41 126/42 159), aged 36 years on average, living in a large metropolitan area (73·8%, 31 096/42 159), and among whom a minority (7·0%, 2966/42 159) were socio-economically disadvantaged. Throughout the study period, 80-90% of users renewed PrEP from one semester to another, suggesting a good level of maintenance among those engaged in treatment. Nevertheless, for 20·1% (7148/35 549) of new PrEP users no prescription renewal was recorded in the first six months after initiation, suggesting a substantial proportion of early treatment discontinuation. Private practitioners accounted for a minority (21·3%, 77 885/366 399) of PrEP renewal prescriptions.PrEP roll-out has been markedly impacted by the COVID-19 pandemic in France. Although PrEP deployment has been substantial among men who have sex with men, further action is needed to expand access to PrEP to all other population groups who could benefit from it and to promote adherence to treatment.This research was carried out within EPI-PHARE without external funding.
Obesity Dysregulates the Immune Response to Influenza Infection and Vaccination Through Metabolic and Inflammatory Mechanisms
Authors: Saame Raza Shaikh, Nancie J. MacIver, Melinda A. Beck
Journal: Annual Review of Nutrition (2022)

The COVID-19 pandemic demonstrates that obesity alone, independent of comorbidities, is a significant risk factor for severe outcomes from infection. This susceptibility mirrors a similar pattern with influenza infection; that is, obesity is a unique risk factor for increased morbidity and mortality. Therefore, it is critical to understand how obesity contributes to a reduced ability to respond to respiratory viral infections. Herein, we discuss human and animal studies with influenza infection and vaccination that show obesity impairs immunity. We cover several key mechanisms for the dysfunction. These mechanisms include systemic and cellular level changes that dysregulate immune cell metabolism and function in addition to how obesity promotes deficiencies in metabolites that control the resolution of inflammation and infection. Finally, we discuss major gaps in knowledge, particularly as they pertain to diet and mechanisms, which will drive future efforts to improve outcomes in response to respiratory viral infections in an increasingly obese population.
Covid-19: Results from India’s 12 molnupiravir clinical trials remain unpublished
Authors: Elisabeth Mahase
Journal: BMJ (2022)

The results of 12 clinical trials conducted in India looking at the efficacy of molnupiravir -an antiviral drug for covid-19-have not been published a year after completion, researchers have said.Researchers from St George's, Imperial College London, and the University of Liverpool looked at the availability of data from these trials as of July 2022 for a study released as a preprint. 1They found that, while some details of the findings had been revealed through press releases or conference abstracts, none of the results had been published in a journal or preprint service.This equates to missing data for 13 694 trial participants."Patient level data would help answer many of the unanswered questions around the molnupiravir trials; however, even summary data are largely absent," the authors wrote.
CNest: A novel copy number association discovery method uncovers 862 new associations from 200,629 whole-exome sequence datasets in the UK Biobank
Authors: Tomas Fitzgerald, Ewan Birney
Journal: Cell Genomics (2022)

Copy number variation (CNV) is known to influence human traits, having a rich history of research into common and rare genetic disease, and although CNV is accepted as an important class of genomic variation, progress on copy-number-based genome-wide association studies (GWASs) from next-generation sequencing (NGS) data has been limited. Here we present a novel method for large-scale copy number analysis from NGS data generating robust copy number estimates and allowing copy number GWASs (CN-GWASs) to be performed genome-wide in discovery mode. We provide a detailed analysis in the UK Biobank resource and a specifically designed software package. We use these methods to perform CN-GWAS analysis across 78 human traits, discovering over 800 genetic associations that are likely to contribute strongly to trait distributions. Finally, we compare CNV and SNP association signals across the same traits and samples, defining specific CNV association classes.
Spatial intra-tumor heterogeneity is associated with survival of lung adenocarcinoma patients
Authors: Hua-Jun Wu, Daniel Temko, Zoltan Maliga, Andre L. Moreira, Emi Sei, Darlan Conterno Minussi, Jamie Dean, Charlotte Lee, Qiong Xu, Guillaume Hochart, Connor A. Jacobson, Clarence Yapp, Denis Schapiro, Peter K. Sorger, Erin H. Seeley, Nicholas Navin, Robert J. Downey, Franziska Michor
Journal: Cell Genomics (2022)

Intra-tumor heterogeneity (ITH) of human tumors is important for tumor progression, treatment response, and drug resistance. However, the spatial distribution of ITH remains incompletely understood. Here, we present spatial analysis of ITH in lung adenocarcinomas from 147 patients using multi-region mass spectrometry of >5,000 regions, single-cell copy number sequencing of ∼2,000 single cells, and cyclic immunofluorescence of >10 million cells. We identified two distinct spatial patterns among tumors, termed clustered and random geographic diversification (GD). These patterns were observed in the same samples using both proteomic and genomic data. The random proteomic GD pattern, which is characterized by decreased cell adhesion and lower levels of tumor-interacting endothelial cells, was significantly associated with increased risk of recurrence or death in two independent patient cohorts. Our study presents comprehensive spatial mapping of ITH in lung adenocarcinoma and provides insights into the mechanisms and clinical consequences of GD.
Up-Regulation of the Error-Prone DNA Polymerase κ Promotes Pleiotropic Genetic Alterations and Tumorigenesis
Authors: Clarisse Bavoux, Andréia Machado Leopoldino, Valérie Bergoglio, Jiyang O-Wang, Tomoo Ogi, Anne Bieth, Jean-Gabriel Judde, Sérgio Danilo Junho Pena, Marie-France Poupon, Thomas Helleday, Masatoshi Tagawa, CarlosRenato Machado, Jean-Sébastien Hoffmann, Christophe Cazaux
Journal: Cancer Research (2005)

Abstract It is currently widely accepted that genetic instability is key to cancer development. Many types of cancers arise as a consequence of a gradual accumulation of nucleotide aberrations, each mutation conferring growth and/or survival advantage. Genetic instability could also proceed in sudden bursts leading to a more drastic upheaval of structure and organization of the genome. Genetic instability, as an operative force, will produce genetic variants and the greater the instability, the larger the number of variants. We report here that the overexpression of human DNA polymerase κ, an error-prone enzyme that is up-regulated in lung cancers, induces DNA breaks and stimulates DNA exchanges as well as aneuploidy. Probably as the result of so many perturbations, excess polymerase κ favors the proliferation of competent tumor cells as observed in immunodeficient mice. These data suggest that altered regulation of DNA metabolism might be related to cancer-associated genetic changes and phenotype.
Third Universal Definition of Myocardial Infarction
Authors: Kristian Thygesen, Joseph S Alpert, Allan S Jaffe, Maarten L Simoons, Bernard R Chaitman, Harvey D White, Hugo A Katus, Bertil Lindahl, David A Morrow, Peter M Clemmensen, Per Johanson, Hanoch Hod, Richard Underwood, Jeroen J Bax, Robert O Bonow, Fausto Pinto, Raymond J Gibbons, Keith A Fox, Dan Atar, L Kristin Newby, Marcello Galvani, Christian W Hamm, Barry F Uretsky, Ph Gabriel Steg, William Wijns, Jean-Pierre Bassand, Phillippe Menasché, Jan Ravkilde, E Magnus Ohman, Elliott M Antman, Lars C Wallentin, Paul W Armstrong, Maarten L Simoons, James L Januzzi, Markku S Nieminen, Mihai Gheorghiade, Gerasimos Filippatos, Russell V Luepker, Stephen P Fortmann, Wayne D Rosamond, Dan Levy, David Wood, Sidney C Smith, Dayi Hu, José-Luis Lopez-Sendon, Rose Marie Robertson, Douglas Weaver, Michal Tendera, Alfred A Bove, Alexander N Parkhomenko, Elena J Vasilieva, Shanti Mendis
Journal: Circulation (2012)
Towards standardised and valid anthropometric indicators of nutritional status in middle childhood and adolescence
Authors: Natasha Lelijveld, Rukundo K Benedict, Stephanie V Wrottesley, Zulfiqar A Bhutta, Elaine Borghi, Tim J Cole, Trevor Croft, Edward A Frongillo, Chika Hayashi, Sorrel Namaste, Deepika Sharma, Alison Tumilowicz, Jonathan C Wells, Majid Ezzati, George C Patton, Emily Mates
Journal: The Lancet Child & Adolescent Health (2022)
Electrospun patch delivery of anti-TNFα F(ab) for the treatment of inflammatory oral mucosal disease
Authors: Jake G. Edmans, Bethany Ollington, Helen E. Colley, Martin E. Santocildes-Romero, Lars Siim Madsen, Paul V. Hatton, Sebastian G. Spain, Craig Murdoch
Journal: Journal of Controlled Release (2022)

Chronic ulcerative oral mucosal inflammatory diseases, including oral lichen planus and recurrent aphthous stomatitis, are painful and highly prevalent, yet lack effective clinical management. In recent years, systemic biologic therapies, including monoclonal antibodies that block the activity of cytokines, have been increasingly used to treat a range of immune-mediated inflammatory conditions such as rheumatoid arthritis and psoriasis. The ability to deliver similar therapeutic agents locally to the oral epithelium could radically alter treatment options for oral mucosal inflammatory diseases, where pro-inflammatory cytokines, in particular tumour-necrosis factor-α (TNFα), are major drivers of pathogenesis. To address this, an electrospun dual-layer mucoadhesive patch comprising medical-grade polymers was investigated for the delivery of F(ab) biologics to the oral mucosa. A fluorescent-labelled F(ab) was incorporated into mucoadhesive membranes using electrospinning with 97% v/v ethanol as a solvent. The F(ab) was detected within the fibres in aggregates when visualised by confocal microscopy. Biotinylated F(ab) was rapidly eluted from the patch (97 ± 5% released within 3 h) without loss of antigen-binding activity. Patches applied to oral epithelium models successfully delivered the F(ab), with fluorescent F(ab) observed within the tissue and 5.1 ± 1.5% cumulative transepithelial permeation reached after 9 h. Neutralising anti-TNFα F(ab) fragments were generated from whole IgG by papain cleavage, as confirmed by SDS-PAGE, then incorporated into patches. F(ab)-containing patches had TNFα neutralising activity, as shown by the suppression of TNFα-mediated CXCL8 release from oral keratinocytes cultured as monolayers. Patches were applied to lipopolysaccharide-stimulated immune-competent oral mucosal ulcer equivalents that contained primary macrophages. Anti-TNFα patch treatment led to reduced levels of active TNFα along with a reduction in the levels of disease-implicated T-cell chemokines (CCL3, CCL5, and CXCL10) to baseline concentrations. This is the first report of an effective device for the delivery of antibody-based biologics to the oral mucosa, enabling the future development of new therapeutic strategies to treat painful conditions.
A multi-tissue atlas of regulatory variants in cattle
Authors: Shuli Liu, Yahui Gao, Oriol Canela-Xandri, Sheng Wang, Ying Yu, Wentao Cai, Bingjie Li, Ruidong Xiang, Amanda J. Chamberlain, Erola Pairo-Castineira, Kenton D’Mellow, Konrad Rawlik, Charley Xia, Yuelin Yao, Pau Navarro, Dominique Rocha, Xiujin Li, Ze Yan, Congjun Li, Benjamin D. Rosen, Curtis P. Van Tassell, Paul M. Vanraden, Shengli Zhang, Li Ma, John B. Cole, George E. Liu, Albert Tenesa, Lingzhao Fang
Journal: Nature Genetics (2022)
Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease
Authors: Marta Milà-Alomà, Nicholas J. Ashton, Mahnaz Shekari, Gemma Salvadó, Paula Ortiz-Romero, Laia Montoliu-Gaya, Andrea L. Benedet, Thomas K. Karikari, Juan Lantero-Rodriguez, Eugeen Vanmechelen, Theresa A. Day, Armand González-Escalante, Gonzalo Sánchez-Benavides, Carolina Minguillon, Karine Fauria, José Luis Molinuevo, Jeffrey L. Dage, Henrik Zetterberg, Juan Domingo Gispert, Marc Suárez-Calvet, Kaj Blennow
Journal: Nature Medicine (2022)

Abstract Blood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer’s disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed in preclinical Alzheimer’s disease. However, plasma p-tau231 reached abnormal levels with the lowest Aβ burden. Plasma p-tau231 and p-tau217 had the strongest association with Aβ positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aβ PET uptake in individuals without overt Aβ pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aβ changes, before overt Aβ plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer’s disease clinical trials.
In vivo visualization and molecular targeting of the cardiac conduction system
Authors: William R. Goodyer, Benjamin M. Beyersdorf, Lauren Duan, Nynke S. van den Berg, Sruthi Mantri, Francisco X. Galdos, Nazan Puluca, Jan W. Buikema, Soah Lee, Darren Salmi, Elise R. Robinson, Stephan Rogalla, Dillon P. Cogan, Chaitan Khosla, Eben L. Rosenthal, Sean M. Wu
Journal: Journal of Clinical Investigation (2022)

Accidental injury to the cardiac conduction system (CCS), a network of specialized cells embedded within the heart and indistinguishable from the surrounding heart muscle tissue, is a major complication in cardiac surgeries. Here, we addressed this unmet need by engineering targeted antibody-dye conjugates directed against the CCS, allowing for the visualization of the CCS in vivo following a single intravenous injection in mice. These optical imaging tools showed high sensitivity, specificity, and resolution, with no adverse effects on CCS function. Further, with the goal of creating a viable prototype for human use, we generated a fully human monoclonal Fab that similarly targets the CCS with high specificity. We demonstrate that, when conjugated to an alternative cargo, this Fab can also be used to modulate CCS biology in vivo, providing a proof of principle for targeted cardiac therapeutics. Finally, in performing differential gene expression analyses of the entire murine CCS at single-cell resolution, we uncovered and validated a suite of additional cell surface markers that can be used to molecularly target the distinct subcomponents of the CCS, each prone to distinct life-threatening arrhythmias. These findings lay the foundation for translational approaches targeting the CCS for visualization and therapy in cardiothoracic surgery, cardiac imaging, and arrhythmia management.
Somatic mutations in single human cardiomyocytes reveal age-associated DNA damage and widespread oxidative genotoxicity
Authors: Sangita Choudhury, August Yue Huang, Junho Kim, Zinan Zhou, Katherine Morillo, Eduardo A. Maury, Jessica W. Tsai, Michael B. Miller, Michael A. Lodato, Sarah Araten, Nazia Hilal, Eunjung Alice Lee, Ming Hui Chen, Christopher A. Walsh
Journal: Nature Aging (2022)

Abstract The accumulation of somatic DNA mutations over time is a hallmark of aging in many dividing and nondividing cells but has not been studied in postmitotic human cardiomyocytes. Using single-cell whole-genome sequencing, we identified and characterized the landscape of somatic single-nucleotide variants (sSNVs) in 56 single cardiomyocytes from 12 individuals (aged from 0.4 to 82 years). Cardiomyocyte sSNVs accumulate with age at rates that are faster than in many dividing cell types and nondividing neurons. Cardiomyocyte sSNVs show distinctive mutational signatures that implicate failed nucleotide excision repair and base excision repair of oxidative DNA damage, and defective mismatch repair. Since age-accumulated sSNVs create many damaging mutations that disrupt gene functions, polyploidization in cardiomyocytes may provide a mechanism of genetic compensation to minimize the complete knockout of essential genes during aging. Age-related accumulation of cardiac mutations provides a paradigm to understand the influence of aging on cardiac dysfunction.
Are SARS-CoV-2 viral loads in children lower than in adults?
Authors: Gülsüm İclal Bayhan, Irmak Özkubat Korkmaz, Enes Seyda Şahiner, Nazlı Tekeli, Ahmet Gökhan Akdağ, Ayşegül Zehra Uyan Erten, Asuman Begüm Taşbaşı, Burak Göre, Mustafa Doğru, Fisun Kırca, Bedia Dinç
Journal: Journal of Infection (2022)
The Autism Biomarkers Consortium for Clinical Trials: Initial Evaluation of a Battery of Candidate EEG Biomarkers
Authors: Sara Jane Webb, Adam J. Naples, April R. Levin, Gerhard Hellemann, Heather Borland, Jessica Benton, Carter Carlos, Takumi McAllister, Megha Santhosh, Helen Seow, Adham Atyabi, Raphael Bernier, Katarzyna Chawarska, Geraldine Dawson, James Dziura, Susan Faja, Shafali Jeste, Michael Murias, Charles A. Nelson, Maura Sabatos-DeVito, Damla Senturk, Frederick Shic, Catherine A. Sugar, James C. McPartland
Journal: American Journal of Psychiatry (2022)

Numerous candidate EEG biomarkers have been put forward for use in clinical research on autism spectrum disorder (ASD), but biomarker development has been hindered by limited attention to the psychometric properties of derived variables, inconsistent results across small studies, and variable methodology. The authors evaluated the basic psychometric properties of a battery of EEG assays for their potential suitability as biomarkers in clinical trials.